In 1638 he embarked at Genoa for Spain to negotiate a league with Philip III against France, but suffering shipwreck on the coast of Provence, he was seized and by order of Cardinal Richelieu imprisoned at Vincennes, where he remained two years, and was only released on promise of his brother the king of Poland never to wage war against France. He then travelled through various countries of western Europe, entered the order of Jesuits in Rome, was made cardinal by Innocent X, however, after his return to Poland he again became a layman, and, having succeeded his brother in 1648, married his widow, Queen Marie Louise Gonzaga. His reign commenced amid the confusion and disasters caused by the great revolt of the Cossacks under Chmielnicki, who had advanced into the very heart of Poland. The power of the king had been stripped of almost all its prerogatives by the growing influence of the nobles.

Russia and Sweden, which had long been active enemies of Poland, availed themselves of its distracted condition, and renewed their attacks. George II Rakoczy of Transylvania too, invaded the Polish territory, while diet after diet was dissolved by abuses of the liberum veto. Charles X Gustav of Sweden triumphantly marched through the country, and occupied Kraków (1655), John Casimir having fled to Silesia. Before Częstochowa, however, the Swedes met with an unexpected check, and a confederation of the nobles against all enemies of the country having been formed, Stefan Czarniecki won a series of victories over the Swedes, Transylvanians, Cossacks, and Russians. The wars with the Swedes and Russians were terminated by treaties involving considerable cessions of provinces on the Baltic and the Dnieper on the part of Poland, which also lost its sway over the Cossacks, who put themselves under the protection of the czar. During these long disturbances John Casimir, though feeble and of a peaceful disposition, frequently proved his patriotism and bravery.

The intrigues of his wife in favor of the duke of Enghien, son of the prince of Con-de, as successor to the throne, having brought about a rebellion under Hetman Jerzy Sebastian Lubomirski, and a bloody though short civil war, the king finally resolved upon abdication, and resigned his crown at the diet of Warsaw on September 16, 1668. In the following year he retired to France, where he was hospitably treated by Louis XIV. His wife had died without issue before his abdication.

John Casimir's reign was one of the most disastrous in the history of Poland, whose dismemberment by the houses of Moscow, Brandenburg, and Habsburg, as it took place 100 years after his death, he predicted in a memorable speech to the diet of 1661.